Neuronal cell death in brain ischemia is partly due to overactivation of glutamate receptors (excitotoxicity), leading to an [Ca^2+]i overload and overactivation of calpains, a group of Ca²⁺-dependent proteases (Prog Neurobiol 143:1-35 [2016]). We have shown that calpains downregulate BDNF-TrkB receptor signaling  as well as GDNF-Ret signaling in brain ischemia with an impact on neuronal demise (J Neurosci 31: 4622-4635 [2012]; Cell Death Dis 6, e1645 [2015]). Furthermore, we reported that overactivation of extrasynaptic glutamate receptors contributes to a dysregulation of the ubiquitin-proteasome system (UPS) under excitotoxic conditions (Biochim Biophys Acta – Mol Basis Dis 1832: 263-274 [2013]), which may also have an impact in the neuronal proteome. Ongoing studies address i) the molecular mechanisms contributing to the impairment of the UPS in brain ischemia, ii) the functional consequences of the UPS dysregulation in brain ischemia, and iii) the putattive neuroprotective effects resulting from activation of the proteasome, iv) development of novel neuroprotective strategies for stroke involving the upregulation BDNF expression. The experimental approaches used to address these questions include the oxygen and glucose deprivation (OGD) model of in vitro ischemia, and the transient middle cerebral artery occlusion model of focal brain ischemia.